The focus of this research is to define the natural history of human papillomavirus (HPV) infection and cervical neoplasia, particularly cofactors that explain why cervical HPV infection (a common sexually-transmitted agent) persists and progresses uncommonly to high-grade neoplasia. Accompanying prevention research on HPV diagnostics attempts to improve cervical cancer screening, while projects on HPV immunology are on the forefront of worldwide etiologic and preventive vaccine development efforts (see closely associated HPV vaccines project. The Portland cohort study of 24,000 women was completed in 2001 but specimen testing and data analyses continue. Using a new HPV DNA test, Hybrid Capture 3, we are evaluating HPV viral load measurements at enrollment and risk of developing cervical precancer and cancer. As a follow-up to our finding of an increased risk of cervical precancer and cancer among oncogenic HPV-infected women who smoke versus those who don?t smoke, we in collaboration with Miriam Poirier (NCI) are measuring smoking-related DNA adduct formation in tissues from these women. Among oncogenic HPV infected women, we will also examine the effects of NSAID use and the development of cervical precancer and cancer. The largest active projects are the Guanacaste cohort analyses and the ALTS clinical trial, both in the testing and analyses phases. Several data analyses are projected for the Guanacaste Project for FY 2004, for example: 1) All aspects of HPV DNA, cytology, and visual appearance of the cervix among the 10,000 women during the 7 years of followup, 2) Evaluation of the role of inflammation in the development of high-grade cervical neoplasia, 3) Examining the relationship of cervical immune profiles and the development of high-grade cervical neoplasia, 4) Age patterns of type-specific prevalent HPV infections, 5) Determinants of HPV16 seroconversion and loss of seroconversion, and 6) The acquisition of sexually transmitted infections and the onset of cervicitis after sexual debut. More than 20 analyses are underway for the ALTS trial of 5,000 women with abnormal cytology followed for 2 years. There are several ancillary projects underway as part of our investigations in Guanacaste. For example, there is a new study called the Cervical Immunity Study of ~500 women who either exited the Guanacaste Study with oncogenic HPV infection or had newly identified CIN2+ within Guanacaste. The primary goal of the study is to examine the relationships of cervical immunity to HPV clearance, persistence, and the development of CIN2+. The field effort is ongoing and is expected to be completed in 2004 with specimen testing and data analyses to ensue. Projects to identify immune genes and the role that innate immunity plays in HPV infection and progression to cervical neoplasia are being sought. Research continues on identifying and validating biomarkers of risk of progression is being conducted. This includes the validation of p16INK4a as a biomarker of oncogenic HPV infection and cervical disease, and the identification of novel tumor suppressor genes found to be methylated in cervical neoplasia. A new study has been launched to comprehensively identify biomarkers of risk at each progressive disease stage, aimed to identify the molecular events that are necessary and sufficient for progression to cervical cancer